Obesity is a profound public health issue and an even more alarming problem for patients with schizophrenia, who are obese at rates twice those observed in the general population. The use of certain neuroleptics to treat the symptoms of schizophrenia contributes greatly to weight gain in the illness. Olanzapine and clozapine, for example, can result in substantial weight gain while neuroleptics such as risperidone appear to cause modest weight gain. There is a relatively rich understanding of the molecular mechanisms of these drugs, yet the processes by which they cause metabolic side effects such as obesity are unknown. While imaging studies by our group and others have begun to improve our understanding of the neuronal processes involved in food intake behavior related to obesity in the general population, these mechanisms have not yet been studied in patients with schizophrenia. The overall goals of this proposal are to improve our understanding of the neuronal mechanisms by which neuroleptics contribute to obesity in schizophrenia and to determine whether an intervention such as exercise causes changes in neuronal response that would predict improved regulation of food intake behavior in schizophrenia. These goals will be addressed with two aims. First, we will determine (a) whether neuronal responses to a meal are altered and are related to food intake behaviors in obese compared to lean patients with schizophrenia and (b) whether neuroleptics that cause the most weight gain in patients are associated with greater alterations in neuronal responses related to food intake behavior compared to those associated with less weight gain. Second, this project will determine if a 12-week exercise intervention, as compared to diet, improves function of brain networks associated with food intake behavior in patients with schizophrenia. Understanding the potential mechanisms of dysregulated or altered food intake in patients with schizophrenia and the effect of neuroleptics will have a significant impact on the field and will elucidate possible mechanisms to help develop better, targeted therapeutic interventions for this population. These goals are in line with both the NIMH Strategic Objective to develop better interventions that incorporate the diverse needs of people with mental illnesses, and the Strategic Plan for NIH Obesity Research, which aims to develop more effective approaches to address the tremendous burden of obesity.